Our proposed research is concerned with plasticity enhancing mechanisms in intact motor cortex (M1) of healthy subjects and lesioned M1 stroke patients.M1 reorganization plays a major-role in the recovery of motor deficits post-stroke;hence the importance for further development of rehabilitative strategies that utilize this potential for recovery. We have shown previously, that motor training combined with d- amphetamine or transcranial magnetic stimulation (IMS) of M1 enhances use-dependent plasticity in intact M1 of healthy subjects. In the proposed study we will further examine modulation of use-dependent plasticity in intact M1 of healthy subjects and lesioned M1 of stroke patients using a combination of electrophysiological, pharmacological and kinematic techniques. Our three specific aims examine IMS of M1 and drugs to enhance use-dependent plasticity in M1. In Specific Aim 1, we will test the effect of drugs that interact specifically with different neurotransmitter systems on use-dependent plasticity in intact M1 of healthy humans as it is not known which systems mediate the beneficial effect of d-amphetamine on use dependent plasticity. In Specific Aim 2, we will identify the parameters, for IMS stimulation of M1 that are most effective to enhance use-dependent plasticity in intact healthy human Ml Specific Aim 3 will assess the efficacy of plasticity enhancing methods developed in intact M1 of healthy subjects (Specific Aims 1 &2) in lesioned M1 of stroke patients by measuring changes in M1 excitability and kinematics of practiced movements. Our proposal links science to neurorehabilitation practice in stroke patients by applying principles known to enhance practice dependent plasticity in intact human M1 to injured M1 of stroke patients to enhance motor recovery. These newly designed rehabilitation strategies could potentially reduce the morbidity and disability of stroke and, thus, reduce dramatically the costs for long-term ambulatory and nursing home care. The positive impact on the field of neurorehabilitation will be considerable.